Compounds of formula 1 wherein R is a methyl, n-propyl or n-butyl group are widely used as local anaesthetics. Biological studies have shown that the (S)-enantiomers of such compounds (e.g. levobupivacaine wherein R is n-butyl) display lower cardiotoxicity than the corresponding racemates whilst maintaining the same anaesthetic potency, and are therefore more beneficial for clinical uses. Thus there is a requirement for efficient processes to manufacture compounds of formula 1 in the form of single enantiomers. The process embodied by the present invention employs a chirality pool approach to levobupivacaine, commencing from L-lysine, an inexpensive starting material which is readily available in bulk.
Although L-lysine has been converted through to optically enriched L-pipecolic acid and esters thereof by diazotisation and cyclisation reactions, cyclisation of an intermediate to form a piperidine-2-carboxanilide directly has hitherto not been reported. Furthermore, in the context of the present invention, these existing methods are hampered by an excessive number of steps required for manipulation of protecting groups in order to obviate Walden inversion at the carboxyl-bearing centre, which leads to the formation of D-pipecolic acid.
An additional benefit of the invention is the provision of unnatural amino acids of formula 2 with (S) configuration, which are important as pharmaceutical intermediates, e.g. for incorporation into physiologically active synthetic peptides. Compound 2a is commonly prepared by a multistep synthesis of the racemate commencing from dihydropyran followed by enzymatic resolution of an ester derivative (e.g. p-nitrobenzyl). This process in inefficient with respect to the number of steps required and by the fact that resolution produces up to 50% of an unwanted enantiomer. Diazotisation of L-lysine and derivatives thereof has been identified as an alternative strategy for the preparation of 2-amino-6-hydroxyhexanoic acid and derivatives thereof. However, such an approach has hitherto only been applied to the synthesis of compound 2c, but this process, employing sodium nitroprusside, is low yielding (28%).
Copper complexation of lysine and similar amino-acids has been extensively used as a technique for temporary protection of the .alpha.-amino acid moiety, as disclosed by Ledger et al, Anstr. J. Chem. 18:933-5 (1965). This procedure facilitates selective transformation of the second amino group present in the side-chain, e.g. the attachment of a covalently-bonded amino-protecting group.